Targeting DNA Methyltransferase 1 Limits Vesicular Stomatitis Virus Through Enhancing IRF3/IFN Signaling

Background: Viruses develop strategies to escape from host anti-viral response in many aspects including hijacking host epigenetic factors. However, the relationship between host DNA methyltransferase 1 (DNMT1) and vesicular stomatitis virus (VSV) replication is largely unknown. Methods: In the present study, we performed Western Blotting, qRT-PCR, RNA interference, Methylation-specific PCR and Cell viability assay to uncover the role of DNMT1 in the process of VSV replication. Results: We have observed VSV infection enhances DNMT1 protein accumulation in macrophage cell. Furthermore, DNMT1 functional blocking and gene silencing limit VSV replication. Moreover, loss of DNMT1 increases interferon responses, including Ifnb1 and IFN-stimulated genes (ISGs) upregulation. CpG islands (CGIs) of Irf3 promoter region are demethylated after DNMT1 short-term inhibition with thioguanine, which is accompanied by Irf3 transcript upregulation. Meanwhile, Irf3 silencing largely reversed DNMT1 loss-suppressed VSV replication. What is more, the basal level of endogenous retrovirus (ERV) transcripts is required for thioguanine-induced ISGs. Conclusions: DNMT1 loss-induced IRF3 enhancement leads to interferon responses and subsequent VSV suppression, which provides a potential strategy to inhibit viral replication by targeting DNMT1 with its inhibitor.